GALNS – Mucopolysaccharidosis Type IVA

Mucopolysaccharidosis Type IVA (Morquio A) is an autosomal recessive lysosomal storage disorder characterized by deficiency of the N-acetylgalactosamine-6-sulfate sulfatase enzyme. The GALNS gene encodes this enzyme, and bi-allelic pathogenic variants lead to impaired keratan sulfate and chondroitin-6-sulfate degradation in multiple tissues. Clinically, affected individuals present with growth delay, spondyloepiphyseal dysplasia, corneal clouding, and cardiopulmonary involvement, with severity correlating with residual enzyme activity.

Genetic evidence includes over 200 unrelated probands harboring compound heterozygous or homozygous GALNS variants across diverse populations. A classic example is c.280C>T (p.Arg94Cys), identified alongside c.289T>G (p.Phe97Val) in a mild MPS IVA case with ∼20% residual activity (PMID:8826435). Founder effects have been reported for c.319+2T>C in Chilean cohorts (n = 10 of 12 patients) (PMID:37901859). The extensive allelic heterogeneity includes missense, nonsense, splice-site, and small indel variants.

Inheritance is strictly autosomal recessive, with compound heterozygosity demonstrated in multiple family studies. Segregation analyses confirm co-segregation of pathogenic alleles with disease in families, though formal counts of additional affected relatives are limited in published reports.

Functional assays have consistently shown that missense mutations destabilize GALNS precursor processing, reduce catalytic efficiency, or impair folding. Transfection experiments reveal severe enzyme deficiency for p.Arg94Cys and p.Phe97Val mutants in fibroblast models (PMID:8826435), while structural analyses of 65 missense variants map severe alleles to the hydrophobic core and mild alleles to surface regions, supporting misfolding as a key pathogenic mechanism (PMID:10814710).

Genotype–phenotype correlations show that variants located in buried residues or causing premature stop codons are associated with severe MPS IVA, whereas surface-exposed missense changes often result in attenuated phenotypes with residual activity up to 13% of wild type (PMID:7668283). These correlations aid prognostication and therapeutic decision-making, including timing of enzyme replacement therapy.

In summary, there is definitive evidence that biallelic GALNS variants cause MPS IVA. Genetic testing of GALNS is essential for early diagnosis, carrier detection, and genotype-guided management. Functional and structural data underscore a haploinsufficiency and misfolding mechanism, providing robust support for diagnostic and therapeutic strategies.

References

• American Journal of Medical Genetics • 1996 • Heteroallelic missense mutations of the galactosamine-6-sulfate sulfatase (GALNS) gene in a mild form of Morquio disease (MPS IVA). PMID:8826435
• American Journal of Human Genetics • 1995 • Mucopolysaccharidosis IVA: identification of a common missense mutation I113F in the N-Acetylgalactosamine-6-sulfate sulfatase gene. PMID:7668283
• Human Molecular Genetics • 2000 • Biochemical and structural analysis of missense mutations in N-acetylgalactosamine-6-sulfate sulfatase causing mucopolysaccharidosis IVA phenotypes. PMID:10814710
• Molecular Syndromology • 2023 • Genotype and Phenotype Characterization of Patients with Mucopolysaccharidosis IV-A in Chile. PMID:37901859

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